Antimicrobial wraps for medical implants

ABSTRACT

Biodegradable antimicrobial films are provided that are solid at room temperature and substantially liquefy in situ after implantation into a mammal, such as a human patient. Methods of using the films to cover a medical device, such as a breast implant, prior to insertion into a subject are also provided.

This application is a national phase application under 35 U.S.C. §371 ofInternational Application No. PCT/US2014/034556, filed Apr. 17, 2014,which claims the benefit of U.S. Provisional Patent Application No.61/813,564, filed Apr. 18, 2013, the entirety of each of which isincorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates generally to the field of medicine. Moreparticularly, it concerns antimicrobial films and coverings for medicaldevices, and related methods.

2. Description of Related Art

Breast reconstruction is frequently performed following mastectomies.Breast implants or tissue expanders are frequently used. Infection is asignificant problem associated with breast implants and tissue expandersfor recovering cancer patients. Infection rates for reconstruction caseshave been estimated to range from 2-24% (Pittet et al.). Other than thedirect systemic complications of infection, local complications cancause discomfort, cosmesis, capsule formation and hardening and can leadto implant removal or replacement. Current protocol is to bathe breastimplant and tissue expander devices in an aqueous solution of threedifferent antibiotics for 5-15 minutes prior to insertion. Most implantsare made from silicone rubber which is highly hydrophobic so theantibiotic solution rolls off the device after it is removed from theantibiotic bath, hence very little antibiotic is actually carried intothe implant tissue pocket following insertion. In a retrospective studyof breast implant infections following reconstructive surgery, 79% ofcases had appropriate antibiotic irrigation performed prior to placementbut 63% had breakthrough infections despite that (Viola et al., 2014).

Following insertion, a drainage catheter is usually left in place for aweek or so which can be a conduit for bacterial access to the device.Furthermore, although the skin flap is eventually closed, breast tissuehas high levels of endogenous bacterial flora that can access andcolonize the device. The factors create a prolonged need for infectionprotection beyond the insertion procedure itself that is not met usingthe current standard of care. The bathing procedure adds to valuable ORtime and because of the size of the implant, significant volumes ofantibiotic solution are required to bathe the implant. Clearly, there isa need for methods for reducing the risk of infection associated withimplanting a medical device or prosthesis, such as a breast implant.

SUMMARY OF THE INVENTION

The present invention overcomes limitations in the prior art byproviding, in certain aspects, biodegradable antimicrobial films thatmay be wrapped around a medical implant or prosthesis, such as a breastimplant, prior to insertion into a subject such as a human patient. Theantimicrobial films may display a melting temperature of less than 38°C.; thus, after insertion into the subject, the film may melt andrelease antimicrobial agents into the immediate vicinity of the implant.In this way, increased amounts of antimicrobial agents and/or additionaltherapeutics may be delivered around substantially all of the surfacesof an implant. Further, since all or part of the antimicrobial film maymelt in situ within several minutes, e.g., from about 1 to less than 15minutes, which may allow for a more thorough delivery of theantimicrobial agents to the surfaces of the implant as well as improvedpharmacokinetics for release of the antimicrobial agents around themedical implant. The antimicrobial agents may reduce or substantiallyprevent infection resulting from a bacteria or fungi. In someembodiments the biodegradable antimicrobial film comprises a highlyplasticized gelatin. In various embodiments, the antimicrobial film maybe subjected to dehydrothermal treatment to increase the working timeand/or toughness. The plasticizer content of a highly plasticizedgelatin may be adjusted to increase ductility; as shown in the belowexamples, increased amounts of plasticizer (e.g., 31-60% glycerol) maybe included in the highly plasticized gelatin to increase the ductility.In some embodiments, the films may contain multiple layers and/orregions comprising antimicrobial compounds and regions that do notcontain antimicrobial compounds.

An aspect of the present invention relates to a biodegradable coveringfor a medical implant, the covering comprising a highly plasticizedgelatin and at least one drug to reduce infection or capsularcontraction, wherein the plasticized gelatin has a melting temperatureof less than about 38° C. In some embodiments, the covering may furthercomprise a lipid-based wax with a T_(m) of about 27-38° C. In someembodiments, it may be possible to substitute a meltable wax with aT_(m) of 27-38° C. for the highly plasticized gelatin. The plasticizedgelatin may have a melting temperature of about 27-37° C. or 30-37° C.The plasticized gelatin may comprise about 31-60% plasticizer. Theplasticizer may be glycerol, a propylene glycol, a sugar, acarbohydrate, an amino acid, a salt, an acid, or a polyol. In someembodiments, the plasticizer is glycerol. In some embodiments, at leasta portion of an inner surface of the covering is substantially sticky oradhesive, and a portion of or substantially all of an outer surface ofthe covering is substantially lubricious. At least a portion of asurface of the covering may be treated with a gluconic acid solution. Atleast a portion of a surface of the covering may be treated with aglycerol-gelatin liquid comprising about 60-90% glycerol or a solution(e.g., a concentrated biodegradable solution) comprising a carbohydrate,a starch, or a sugar; such solutions may be useful for causing theportion of the surface to become substantially sticky or adhesive. Thecovering may be sufficient in size or shaped to cover a breast implant.The covering may be shaped as a film, a wrap, a pouch or a bag. In someembodiments, the covering is a pouch or a bag; wherein the covering hasa central region and a plurality of lateral appendages, or the coveringis substantially star-shaped. The covering may comprise a plurality ofbiodegradable layers. The at least one drug may be selected from thegroup consisting of an antimicrobial agent, an anti-inflammatory agent,an anti-scarring agent, a hemostatic agent, an anti-neoplastic agent, acalcium channel blocker, and a leukotriene inhibitor. The at least onedrug may be comprised in a fiber, a bead, a particle, a liposome, amicrosphere, or a nanosphere. The at least one drug may be anantimicrobial agent such as, e.g., bacitracin, cephalexin, gentamicin,an antiseptic, a chelator, chlorhexidine, gendine, gardine, or mixturesthereof. The antiseptic may be hydrogen peroxide, chlorhexidine,gendine, or gardine. In some embodiments, the covering further comprisesmercaptoethane sulfonate (MeSNA), minocycline, rifampin, glyceryltrinitrate (GTN). The covering may further comprise a nitroglycerin ornitric oxide donor. The at least one drug may be a leukotrieneinhibitor. The leukotriene inhibitor may be a leukotriene receptorantagonist selected from the group consisting of acitazanolast,iralukast, montelukast, pranlukast, verlukast, zafirlukast, andzileuton. The covering may comprise at least one, two, three, or all ofmercaptoethane sulfonate (MeSNA), minocycline, rifampin, or glyceryltrinitrate (GTN). In some embodiments, the covering comprisesminocycline, rifampin, and mercaptoethane sulfonate. In someembodiments, the covering further comprises glyceryl trinitrate (GTN).

In some embodiments, the covering further comprises a fatty acid ormonoglyceride. The fatty acid may be a C₆₋₁₂ alkanoic acid or a C₆₋₁₀alkanoic acid. The fatty acid may be hexanoic acid, octanoic acid,decanoic acid, dodecanoic acid, caprylic acid (octanoic acid), caproicacid, or lauric acid. In some embodiments, the fatty acid is caprylicacid (octanoic acid). The covering may further comprise glyceryltrinitrate (GTN) and capyrilic acid.

In some embodiments, at least a portion of the covering has been exposedto crosslinking. In some embodiments, at least half of the covering hasbeen exposed to crosslinking. The crosslinking may comprise exposing atleast a portion of the covering to radiation. In some embodiments, thecrosslinking comprises exposing at least a portion of the covering to adehydrothermal heat treatment. The crosslinking may be further definedas mild or partial crosslinking (e.g., incomplete crosslinking resultingfrom dehydrothermal heat treatment). In some embodiments, thecrosslinking is sufficient to increase the working time, toughness, orstiffness of the covering. Said portion may comprise an antimicrobialagent such as, e.g., minocycline, rifampin, chlorhexidine, gendine, orgardine. In some embodiments, said portion comprises minocycline andrifampin. Said portion may further comprise mercaptoethane sulfonate(MeSNA), glyceryl trinitrate (GTN), or a C₆₋₁₀ alkanoic acid (e.g.,caprylic acid).

In some embodiments, the covering comprises regions that have beenexposed to crosslinking and regions that have not been exposed tocrosslinking. In some embodiments, the regions that have not beenexposed to crosslinking comprise the drug, and wherein the regions thathave been exposed to crosslinking do not comprise the drug. In someembodiments, both the regions that have not been exposed to crosslinkingand the regions that have been exposed to crosslinking both comprise thedrug. In some embodiments, the regions that have not been exposed tocrosslinking comprise the drug, and wherein the regions that have beenexposed to crosslinking do not comprise the drug. The regions that havenot been exposed to crosslinking may comprise minocycline and rifampin.In some embodiments, the regions that have not been exposed tocrosslinking further comprise glyceryl trinitrate (GTN). The regionsthat have not been exposed to crosslinking may further comprisemercaptoethane sulfonate (MeSNA). The regions that have not been exposedto crosslinking may further comprise caprylic acid. In some embodiments,at least a portion of the covering has not been exposed to crosslinking.The covering may comprise or consist of a single layer. The covering maycomprise regions that have been exposed to crosslinking and regions thathave not been exposed to crosslinking. In some embodiments, the drug iscomprised in the regions that have not been exposed to crosslinking. Insome embodiments, the drug is comprised in the regions that have beenexposed to crosslinking. The regions that have not been exposed tocrosslinking may be present in the covering in a pattern of shapes or ina sponge-like pattern. The shapes may comprise a plurality ofsubstantially circular or oval shapes (e.g., in a dotted or polka-dotpattern).

In some embodiments, the covering has multiple layers. The covering mayhave at least 2 layers. In some embodiments, the covering has 2 layers.In some embodiments, a layer has been exposed to crosslinking. The layermay comprise an antimicrobial agent. In some embodiments, the layer hasbeen exposed to a dehydrothermal heat treatment and subsequentlycontacted with a solution containing the antimicrobial agent. The layermay be dried or exposed to a dehydrothermal heat treatment after beingcontacted with said solution. Said solution may comprise an alcohol(e.g., ethanol or methanol) and water. In some embodiments, the alcoholcomprises about 1-50% of the solution. The solution may comprise gelatinand glycerol. In some embodiments, the covering comprises a first layercomprising a partially crosslinked plasticized gelatin and a secondlayer comprising a plasticized gelatin that has not been crosslinked,wherein the second layer comprises the drug. The second layer maycomprise minocycline and rifampin. The highly plasticized gelatin may becomprised in an inner layer or a middle layer of the covering. In someembodiments, an outer layer of the covering has a melting temperature ofgreater than 38° C. The covering may have more than 2 layers, e.g., 3,4, 5, or 6 layers. In some embodiments, the covering has 3 layers,wherein the 3 layers are an outer layer, a middle layer, and an innerlayer. The outer layer of the covering may comprise said drug. The innerlayer of the covering may comprise said drug. In some embodiments, themiddle layer comprises the drug. The middle layer may comprise thehighly plasticized gelatin. In some embodiments, the inner layer and/orthe outer layer has a melting temperature of greater than 38° C. In someembodiments, the outer layer and inner layer have been exposed tocrosslinking. In some embodiments, regions of the middle layer have beenexposed to crosslinking and regions of the middle layer have not beenexposed to crosslinking, wherein said at least one drug is comprised ina least some of the regions that have not been exposed to crosslinking.One or all of the edges of the covering may be melted or weldedtogether. In some embodiments, the covering comprises at least threelayers, and wherein the edges of the outermost layers have been meltedor welded together by the application of heat. In some embodiments, theoutermost layers are partially crosslinked, and wherein an inner layercomprises the highly plasticized gelatin and the drug. The inner layermay comprise minocycline and rifampin. Said application of heat may bevia heat gun, food sealer, or laser. The covering may compriseminocycline and rifampin. The covering may further comprise glyceryltrinitrate (GTN). The covering may further comprises mercaptoethanesulfonate (MeSNA). The covering may further comprise caprylic acid. Insome embodiments, the highly plasticized gelatin comprises (GTN andMeSNA), (GTN and caprylic acid), (MeSNA and caprylic acid), or (GTN,MeSNA, and caprylic acid); additionally, the highly plasticized gelatinmay further comprise minocycline and rifampin. In some embodiments, thehighly plasticized gelatin comprises (minocycline and rifampin),(minocycline, rifampin, and GTN), (minocycline, rifampin, and MeSNA),(minocycline, rifampin, GTN, and MeSNA), (minocycline, rifampin,caprylic acid, and MeSNA), or (minocycline, rifampin, GTN, caprylicacid, and MeSNA).

In some embodiments, the highly plasticized gelatin is comprised on anadhesive backing. The adhesive backing is translucent. The adhesivebacking may be or comprise part of a bandage or wound dressing. In someembodiments, the highly plasticized gelatin is translucent, and whereinbandage or wound dressing allows for viewing of skin or tissue under thebandage or wound dressing. In some embodiments, the bandage or wounddressing is comprised in a kit.

Another aspect of the present invention involves a kit comprising abreast implant and a biodegradable covering of the present invention.

Yet another aspect of the present invention involves a breast implantassembly comprising a biodegradable covering of the present inventioncontaining a breast implant.

Another aspect of the present invention relates to a method for reducingat least one post-surgical indication from breast augmentation or breastreconstruction in a subject, the method comprising surgically implantinginto the subject the breast implant assembly. The biodegradable coveringmay be a film, and the method may further comprise wrapping the breastimplant with the biodegradable covering prior to insertion. The methodmay further comprise trimming excess film prior to said implanting. Thewrapping may occur prior to a surgery for said implantation. In someembodiments, the wrapping occurs during a surgery that comprises saidimplantation. The indication may be selected from the group consistingof infection, inflammation, capsular contracture, adhesion, andscarring. The biodegradable covering may be used to line or cover partor all of a region in the subjects body, wherein the breast implant issubsequently placed on the biodegradable covering, and wherein thecovering is subsequently used to cover the breast implant.

Yet another aspect of the present invention relates to a transcutaneousdevice assembly comprising a biodegradable covering of the presentinvention that is wrapped around at least a portion of thetranscutaneous device. The transcutaneous device may be an electricalnerve stimulation device, a catheter, a screw, a rod, a pin, a wire, acollar, a tube, or a surgical drain. In some embodiments, thetranscutaneous device is a surgical drain.

Another aspect of the present invention relates to a method for reducingat least one post-surgical indication (e.g., infection, inflammation,etc.) from implantation of a transcutaneous device in a subject, themethod comprising surgically implanting into the subject thetranscutaneous device assembly of the present invention. The subject maybe a human patient. In some embodiments, the portion of thetranscutaneous device that is placed in the subject is covered by saidcovering. The transcutaneous device may be secured outside of the bodyof the subject with a wound dressing or bandage.

A variety of medical implants may be covered with a biodegradable filmof the present invention. For example, the medical device may be abreast implant, a penile implant, a cosmetic restorative or enhancementimplant, an implantable prosthesis, or an orthopedic implant, a dentalimplant, an ophthalmic implant, a cranial implant, a cardiac implant, apump, a regulator or a stimulator.

Antimicrobial agents included in the films and wraps as described hereinmay inhibit the growth of or kill a wide variety of genuses and speciesof bacteria and fungi including, e.g., spherical, rod-shaped, and spiralbacteria. Non-limiting examples of bacteria include staphylococci (e.g.,Staphylococcus epidermidis, Staphylococcus aureus), Enterrococcusfaecalis, Pseudomonas aeruginosa, Escherichia coli, among othergram-positive bacteria and gram-negative bacilli. Non-limiting examplesof fungal organisms include Candida albicans and Candida krusei.

A variety of therapeutic compounds may be included in the biodegradablefilms as disclosed herein. These compounds include antibiotics;leukotriene antagonists, such as zafirlukast, montelukast, pranlukastand zileuton; antineoplastic agents, such as 5-fluoruricil; nitric oxideproducing agents, such as L-arginine; calcium-channel blockers, such asverapamil; TNF; interleukins; interferons; paclitaxel or otherchemotherapy agents; 2-mercaptoethanesulfonate; antifungal agents; aswell as any other agent, especially those that are known to for theirability to reduce capsular contracture. Examples of non-steroidalanti-inflammatory agents include, but are not limited to, acetaminophen,aspirin, celecoxib, diclofenac, diflunisal, flurbiprofen, ibuprofen,indomethacin, ketoprofen, ketorolac, meclofenamate, meloxicam, methylsalicylate, nabumetone, naproxen, oxaprozin, piroxicam, sulindac,tolmetin and trolamine. Examples of antimicrobial drugs include, but arenot limited to: aminoglycosides, such as amikacin, gentamicin,kanamycin, neomycin, streptomycin, and tobramycin; antibiotics, such asbacitracin, clindamycin, daptomycin, lincomycin, linezolid, metronid,polymyxin, rifaximin, vancomycin; cephalosporins, such as cephazolin orcephalexin; macrolide antibiotics, such as erythromycin, azithromycinand the like; β-lactam antibiotics, such as penicillins; quinolones,such as ciprofloxacin; sulfonamides, such as sulfadiazine;tetracyclines, such as minocycline and tetracycline; and otherantibiotics, such as rifampin, triclosan, chlorhexidine, gendine, andgardine.

The phrase “a chelator” denotes one or more chelators. As used herein,the term “chelator” is defined as a molecule comprising nonmetal atoms,two or more of which atoms are capable of linking or binding with ametal ion to form a heterocyclic ring including the metal ion.

As used herein the specification, “a” or “an” may mean one or more. Asused herein in the claim(s), when used in conjunction with the word“comprising”, the words “a” or “an” may mean one or more than one.

The use of the term “or” in the claims is used to mean “and/or” unlessexplicitly indicated to refer to alternatives only or the alternativesare mutually exclusive, although the disclosure supports a definitionthat refers to only alternatives and “and/or.” As used herein “another”may mean at least a second or more.

Throughout this application, the term “about” is used to indicate that avalue includes the inherent variation of error for the device, themethod being employed to determine the value, or the variation thatexists among the study subjects.

Other objects, features and advantages of the present invention willbecome apparent from the following detailed description. It should beunderstood, however, that the detailed description and the specificexamples, while indicating preferred embodiments of the invention, aregiven by way of illustration only, since various changes andmodifications within the spirit and scope of the invention will becomeapparent to those skilled in the art from this detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings form part of the present specification and areincluded to further demonstrate certain aspects of the presentinvention. The invention may be better understood by reference to one ormore of these drawings in combination with the detailed description ofspecific embodiments presented herein.

FIG. 1: Growth of test organisms on silicone discs. The presence orabsence of minocycline (Mino) and rifampin (Rifampin) on silicone discsis shown.

FIG. 2: Inhibition of test organisms on silicone discs with minocycline(Mino), rifampin (Rifampin), and GTN.

FIG. 3: Inhibition of clinical strains of MRSA and Pseudomonasaeruginosa. The presence or absence of minocycline and rifampin (M/R),GTN, and/or MeSNA is shown.

FIG. 4: Inhibition of a clinical isolate of MRSA on silicone discs. Thepresence or absence of minocycline and rifampin (M/R), GTN, and/or MeSNAis shown.

FIG. 5: Inhibition of a clinical strain of Pseudomonas aeruginosa. Thepresence or absence of minocycline and rifampin (M/R), MeSNA, and/orcaprylic acid is shown.

FIG. 6: A drawing of a film design containing structural regions oflightly crosslinked gelatin and regions with Minocycline/Rifampin.

FIG. 7: Example of a 3-layer laminate film containing a middle layercomprising antimicrobial compounds.

FIGS. 8A-B: Gelatin wrapped disks had no adverse effect on the viabilityof 293T cells relative to cells grown in broth. Results from Alamar blue(FIG. 8A) and MTT assays (FIG. 8B) are shown. Gelatin wrapped diskscontaining MeSNA, Low M/R, High M/R and MeSNA+Low M/R did not produce asignificant reduction in cell viability compared to cells grown inbroth.

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

In some aspects, flexible solid films containing one or moreantimicrobial or therapeutic agents are provided that can be wrappedaround a medical implant or device prior to implantation in a mammaliansubject. After implantation, the film can rapidly melt due to thetemperature of the subject, e.g., to form a conformal liquid coatingaround the implant or device. The film may be shaped into a bag, apouch, or a covering into which the device is inserted prior toimplantation. The film may substantially melt or liquefy within minutesafter implantation, e.g., about 5-20 minutes, due to the meltingtemperature of the film. The film generally requires sufficientmechanical strength to be able to withstand the wrapping andimplantation steps without fracturing. The film can containantimicrobial agents, analgesic agents, anti-scarring agents,anti-inflammatory agents and/or anti-fibrotic agents. The antimicrobialagents may be encapsulated in fibers or microspheres in order to extendtheir longevities around the implant. The film and encapsulating agentsare preferably bioabsorbable. The film may be coated with an adhesivelayer on one or both sides of the film. In some embodiments, the film islayered such that one side of the film is sticky or adhesive, and mayfacilitate adherence to the medical device, and the other side islubricious to facilitate implantation into a tissue pocket.

Using a biodegradable antimicrobial covering or film that liquefies insitu after insertion into a mammalian subject may provide severaladvantages. For example, in some embodiments, such a covering mayprovide improved comfort immediately following implantation. A liquidcoating would generally not present edges that could be irritating tosoft tissues. In contrast to a solid cover which could tear or createfriction from physically shifting positions within around the implantduring healing, an implant that liquefies in situ after insertion may beable to substantially move within is local environment cover oralternatively the implant would not be impeded. This may be particularlyimportant for tissue expander implants such as breast implants where theshape of the implant is changed in situ over time. Unlike previous solidshaped conformal pouches, such as those described in US20080241212, thatrequire the manufacture of different sized solid pouches to accommodatedifferent size devices, the liquefying films as provided herein may beproduced in a single size to accommodate a wide variety of devices,e.g., by either trimming the film at the point of use or by overwrappingto form a thicker liquid coating. Applying the liquid coating as a solidfor purposes of implantation can provide significant advantages, e.g.,if a coating was applied as a liquid there would be a risk that it couldspill off the side of the device or be scraped off or depressed intothin regions during manipulation in preparation for insertion or duringthe insertion process.

In some embodiments, the film or covering comprises a highly plasticizedgelatin. The highly plasticized gelatin may be substantially oressentially nontoxic. The plasticized gelatin may provide advantagesincluding, e.g., a relatively low cost, improved safety, and apredictable bioabsorption profile. In certain embodiments, the highlyplasticized gelatin can be easily wrapped around an implant or tissueexpanders and molded to their shape such that the device can be insertedwith a conformal wrap. The wrap may melt in-situ within minutesproviding a conformal liquid coating that can deliver antimicrobial (aswell as other) medications to substantially all surfaces of the implant.

I. BIOABSORBABLE PLASTICIZED POLYMERS

In some embodiments, a biodegradable film or covering of the presentinvention comprises a bioabsorbable plasticized polymer such as, e.g., ahighly plasticized gelatin. Generally, the films have a meltingtemperature such that they are substantially solid at room temperature,but will melt or liquefy after insertion into a mammalian subject, suchas a human patient.

In some embodiments, the bioabsorbable plasticized polymer is a highlyplasticized gelatin. Gelatins are protein based colloid solutions thattend to have a defined shape and allow for some movement, but typicallythey may be easily broken with mechanical force. In some embodiments,the strength of a gelatin is increased by introduction of a plasticizer,such as glycerol. In some embodiments, a highly plasticized gelatin maybe produced as described in U.S. Pat. No. 3,042,524 or U.S. Pat. No.5,622,740, which are incorporated by reference herein in their entirety.The plasticizing agent can increase the strength of the film and allowfor the modulation of the melting temperature. In some embodiments, theaddition of plasticizing agents can be used to reduce the meltingtemperature (T_(m)) of a plasticized gelatin to less than 38° C. (e.g.,21-38° C., 25-37.05° C., 29-37° C., etc.).

Plasticized gelatins are distinct and different from gelatin.Plasticized gelatin is displays different physical properties ascompared to gelatin, including increased mechanical strength. The formof plasticized-gelatin taught in U.S. Pat. No. 5,622,740 (containing5-30% plasticizer) is suitable for use as food casings while ordinary,non-plasticized gelatin would have been too weak and susceptible tocracking. In contrast to gelatin, plasticized-gelatin can be processedwith conventional extrusion equipment. The use of conventional extrusionequipment may also provide economic advantages, as compared to gelatin,since this equipment can be used to manufacture large coverings orfilms.

In some embodiments, the plasticized gelatin is a highly plasticizedgelatin containing a plasticizer concentration range of from greaterthan about 30% to about 60%. Highly plasticized-gelatin can displaysufficient strength while in solid form to wrap a medical implant suchas a breast implant, an ability to rapidly melt once implanted, and/oran ability to wrap and conformally adhere to a medical device. In someembodiments, the plasticized-gelatin taught in U.S. Pat. No. 5,622,740,which contain 5-30% plasticizer, are not used since these plasticizedgelatins would be too stiff to wrap and conformally adhere to a medicaldevice without some additional device such as a clip, suture or stapleto secure it and prevent unwrapping. The plasticizer included in thehighly plasticized gelatin may be, e.g., glycerol, a propylene glycol, asugar, or a polyol.

Other bioabsorbable polymers with an appropriate melting temperaturerange may be used in various embodiments. For examples, thebioabsorbable polymer may be a caprolactone based polymer or copolymer,or a trimethylene carbonate polymer or copolymers. In other embodimentswhere irritation to a subject is a concern, caprolactone polymers andtrimethylene carbonate polymers may be avoided, as they can degrade invivo into acidic moieties that may cause irritation. In someembodiments, the bioabsorbable polymer may be a polyphosphazine oramino-acid based polymers. Plasticizers for these polymers include DMSO,benzyl benzoate, glycol furol, and N-methyl pyrrolidone. Certain starchand cellulose-based polymers may also be used in various embodiments. Insome embodiments, the bioabsorbable polymer is a plasticized protein orpolypeptide. The plasticized proteins or polypeptides may be used forforming a convertible solid film. In some embodiments the film cancomprise a solid wax. In some embodiments, meltable wax compositions donot include substantial quantities of lipid-based polyols that can bemetabolized to acidic moieties that become irritating inside the body;for example, Trilucent™ oil filled breast implants caused complicationsresulting by lipid metabolism, and were removed from the market as aresult of inflammatory complications associated with metabolicconversion of lipids that leaked outside of the silicone rubber envelopeof the implants. In some embodiments, the film may comprise a fatty acidsuch as caprylic acid. As shown herein, fatty acids such as caprylicacid may be included in a film, e.g., at a concentration of less thanabout 10%, to improve the antimicrobial properties of the film. fattyacids such as caprylic acid may be included in a film or antimicrobialwrap of the present invention in an amount of, e.g., less than about10%, less than about 5%, 0.01-10%, 0.01-5%, 0.1-5%, 0.5-10%, 0.1-9%,1-8%, 1-7%, 1-6%, or 1-5%.

Additional bioabsorbable plasticizer-polymer combinations that may beused in various embodiments are listed below.

Other Bioabsorbable Plasticizer-Polymer Combinations that May haveTm<38° C.:

BioAbsorbable Polymer Plasticizers Poly lactide coglycolide DMSO,n-METHYL 2-PYRROLIDONE, tetraglycol, glycol fural, propylene carbonate,triacetin, ethyl acetate, benzyl benzoate Poly Caprolactone coglycolideSame as above Poly Caprolactone colactide Same as above Poly Dioxanonecoglycolide Same as above Poly Caprolactone Same as above cotrimethylenecarbonate

II. PLASTICIZERS

A variety of plasticizing agents may be used in various embodiments ofthe present invention, e.g., to alter the physical properties of and/orreduce the melting temperature of a bioabsorbable plasticized polymer.For example, plasticizing agents such as aliphatic polyols, poloxamers,sugars, and polyethylene glycols are contemplated for use in thebioabsorbable highly plasticized polymers. The plasticizer may be anamino acid or a carbohydrate. In some embodiments, the plasticizingagent is glycerol. In some embodiments, the polyols of the formula:

may be used. In some embodiments, the highly plasticized gelatin mayarise from the combination of porcine gelatin and glycerol together. Insome embodiment, the plasticizing agent can be used in percentages ofapproximately 30-60% of the bulk material.

As used herein, the term “highly plasticized” refers to the inclusion offrom greater than about 30 to about 60% of a plasticizer in abioabsorbable polymer. Various ranges of plasticizer may be included ina bioabsorbable polymer such as, e.g., 31-60%, 35-60%, 40-60%, or 35%,40%, 45%, 50%, 55%, 60%, or any range derivable therein.

III. MELTING TEMPERATURES (T_(m)) OF ANTIMICROBIAL FILMS OR WRAPCOMPOSITIONS

In contrast to solid biodegradable covers for medical implants thatremain substantially solid or rubbery after insertion into a mammaliansubject, biodegradable films or covers provided herein have, in variousaspects, a melting temperature that allows for the biodegradable film orcover to remain substantially solid at room temperature (e.g., 15-25°C.), but liquefy after insertion into a mammalian subject.

This prior art does not anticipate a cover that is applied as a solidbut rapidly converts into a liquid upon implantation. By rapidly we meanwithin a sufficient working time to implant a covered device once theimplant site has been prepared. For a breast implant this typicallyrequires several minutes.

In some aspects, the films or wrap compositions used herein may have amelting point of from about 23-36.5° C., about 24-37° C., about 25-37°C., about 30-37° C., or about 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,30, 31, 32, 33, 34, 35, 36, 37, or 38° C., or any range derivabletherein. In addition to the melting temperature, the rate ofliquefaction of the film or wrap (i.e., the rate at which the materialliquefies) can also be affected by the degree of hydration of thematerial. For example, the wrap of film may require hydration forliquefaction; thus, if the wrap or film is more dehydrated (e.g., via adehydrothermal heat treatment), then the film or wrap may hydrate moreslowly and thus liquefy more slowly. The hydrophilicity of theplasticizer or the hydrophilicity of bioactive or antimicrobial agentspresent in the film or wrap may affect the degree of hydration and/orthe rate of hydration of the material after inserted in a subject.Additionally, increased amounts of crosslinking, such as dehydrothermalheat treatment, can make the film tougher and slow the rate ofliquefaction by removing more water from the film or wrap, thus slowingthe liquefaction of the film or wrap after insertion into a subject,such as a human patient. In some embodiments, the melting orliquefaction of a film or wrap of the present invention may take atleast 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or at least 60 minutesafter insertion onto or into a mammalian subject, such as a humanpatient.

The melting point (T_(m)) of a compound is distinct and different fromthe glass transition temperature (T_(g)) of a compound. There areseveral ways to describe the change in ordered structure of a compoundand the temperature upon which that substance undergoes changes. Theclassic description of a melting temperature (T_(m)) relatesspecifically to the changing of a substance which goes from one phase toanother, specifically from a solid phase to a liquid phase. On the otherhand, the glass transition temperature (T_(g)) describes the conversionof an amorphous solid from a brittle solid into a more free flowing orrubbery glass. While a glass transition temperature can be near to themelting temperature, the glass transition temperature is almost alwayslower than the melting temperature. Finally, the glass transitiontemperature does not relate to a true phase transition like a meltingtemperature rather represents a series of different possible changes inproperties such as viscosity of a polymer. Restated, although the glasstransition temperature of the compound may be lower than 38° C., themelting temperature of the compound may not be below that threshold.

IV. ADDITIONAL THERAPEUTIC AGENTS

One or more additional therapeutic agent may be included in anantimicrobial film or pouch of the present invention. The therapeuticagent may be an antimicrobial agent, an anesthetic, an analgesic, ananti-inflammatory agent, an anti-scarring agents, an anti-fibroticagent, an anti-neoplastic agent, and/or a leukotriene inhibitor.

Therapeutic or bioactive agents may be incorporated into a film or coverof the present invention in a variety of ways. For example, one or moretherapeutic agent may be dissolved or emulsified in the plasticizingliquids of the invention, e.g., to ensure a substantially evendispersal, and then the therapeutic agent(s) may be incorporated duringthe formation or synthesis of the film or cover. Alternatively, theycould be suspended in a solid composition prior to forming andsolidifying the films. In some embodiments, a therapeutic agent may befirst encapsulated in fibers, beads, particles, liposomes, microspheresor nanospheres and then dispersed into a film or coating as describedherein. In some embodiments, biodegradable microspheres, biodegradablenanospheres, or phospholipid liposomes may be utilized. Theencapsulating polymers are preferably bioabsorbable. In someembodiments, the encapsulating polymers may degrade or absorb into thesurrounding tissues at a different rates than the film, e.g., to prolongor reduce the rate of release of the therapeutic agent(s) into thesurrounding tissues. The bioactive agent may also be applied as a thinmesh on top of or between film layers in a multilayer film by a varietyof processes including nanospinning. Bioactive agents of interestinclude antimicrobial agents, particularly combinations of minocyclineand rifampin and other antimicrobials, gendine based combinations, andcombinations of antimicrobials with nitroglycerin or nitric oxidedonors. A chelator may be included in a bioabsorbable film of thepresent invention. In addition to antimicrobial agents, an analgesicagent (e.g., lidocaine), an antiscarring agents (e.g., MeSNA), ananti-inflammatory agent (e.g., a steroid), an efflux pump inhibitor(e.g., Verapamil), or an antifibrotic agent (e.g., a TGF-beta inhibitor)may be included in the bioabsorbable film.

In some embodiments, a therapeutic agent as described in US20080241212,US2008128315, US20120052292, US20110082545, US20110082546, orUS20120123535, which are incorporated herein in their entirety, may beincluded in a biodegradable film, pouch, sleeve, or covering, e.g., tofor covering a breast implant, of the present invention.

The therapeutic agent may be an antimicrobial agent such as a rifamycin(e.g., rifampin, rifamycin, rifampicin) and/or a tetracycline antibioticsuch as minocycline. In some embodiments, the bioabsorbable film maycomprise rifampin and minocycline. As shown in the below examples,inclusion of a nitroglycerin or nitric oxide donors, such as glyceryltrinitrate (GTN) may result in a synergistic enchantment of theantimicrobial or bactericidal effects of antibiotics (e.g., minocyclineand rifampin). Inclusion of MeSNA of capyrilic acid may also result in asignificant or synergistic improvement in the antimicrobial effects ofminocycline and rifampin. The bioabsorbable film or covering may furthercomprise an antifungal agent or an antiviral agent.

In some embodiments, a nitroglycerin or nitric oxide donor is includedin the bioabsorbable film. For example, the nitroglycerin or nitricoxide donor may be glyceryl trinitrate (GTN), L-arginine, mono- ordinitrate (such as glycerol mono or dinitrate), nitrosocompound (such asnitrosoglutathione or nitrosocycteine), isosorbide nitrate (such asisosorbide di- or mono-nitrate), a nitroprusside, a diazenium diolate(such as NONOates), a nitric oxide complex (such as nitricoxide-spermine), or an exogenous nitric oxide generating catalyst (suchas reduced silver, copper and other metal ions).

A variety of antibacterial agents may be included in the bioabsorbablefilm. The antimicrobial agent may be an antibacterial agent.Antibacterial agent that may be used include, e.g., aminoglycosides,beta lactams, quinolones or fluoroquinolones, macrolides, sulfonamides,sulfamethaxozoles, tetracyclines, streptogramins, oxazolidinones (suchas linezolid), clindamycins, lincomycins, rifamycins, glycopeptides,polymxins, and lipo-peptide antibiotics. The antibacterial agent may beformulated, e.g., as a pharmacologically acceptable salt, in a lipidformulations, etc. Exemplary aminoglycosides that may be used in somespecific aspects of the invention include amikacin, kanamycin,gentamicin, tobramycin, or netilmicin. Beta lactams are a class ofantibacterials that inhibit bacterial cell wall synthesis. A majority ofthe clinically useful beta-lactams belong to either the penicillin group(penam) or cephalosporin (cephem) groups. The beta-lactams also includethe carbapenems (e.g., imipenem), and monobactams (e.g., aztreonam).Inhibitors of beta-lactamase such as clavulanic acid and its derivativesare also included in this category. Non-limiting examples of thepenicillin group of antibiotics that may be used in the solutions of thepresent invention include amoxicillin, ampicillin, benzathine penicillinG, carbenicillin, cloxacillin, dicloxacillin, piperacillin, orticarcillin, etc. Examples of cephalosporins include ceftiofur,ceftiofur sodium, cefazolin, cefaclor, ceftibuten, ceftizoxime,cefoperazone, cefuroxime, cefprozil, ceftazidime, cefotaxime,cefadroxil, cephalexin, cefamandole, cefepime, cefdinir, cefriaxone,cefixime, cefpodoximeproxetil, cephapirin, cefoxitin, cefotetan etc.Other examples of beta lactams include mipenem or meropenem which areextremely active parenteral antibiotics with a spectrum against almostall gram-positive and gram-negative organisms, both aerobic andanaerobic and to which Enterococci, B. fragilis, and P. aeruginosa areparticularly susceptible. Examples of beta lactamase inhibitors includeclavulanate, sulbactam, or tazobactam. Exemplary macrolides includeerythromycin, azithromycin, clarithromycin. Examples of quinolones andfluoroquinolones include nalidixic acid, cinoxacin, trovafloxacin,ofloxacin, levofloxacin, grepafloxacin, trovafloxacin, sparfloxacin,norfloxacin, ciprofloxacin, moxifloxacin and gatifloxacin. Exemplarysulphonamides include mafenide, sulfisoxazole, sulfamethoxazole, andsulfadiazine. The tetracycline group of antibiotics include tetracyclinederivatives such as tigecycline, minocycline, doxycycline,demeclocycline, anhydrotetracycline, chlorotetracycline, andepioxytetracycline. The streptogramin antibacterial agents includequinupristin and dalfopristin. Other antibacterial drugs includeglycopeptides such as vancomycin and teicoplanin. Other antibacterialdrugs include polymyxins, such as colistin, prestinomycin,chloramphenicol, trimethoprim, fusidic acid, metronidazole, bacitracin,spectinomycin, nitrofurantion, daptomycin or other leptopeptides,oritavancin, dalbavancin, ramoplamin, and ketolide

A variety of chelators may be included in a bioabsorbable film asdisclosed herein. Exemplary chelators include EDTA free acid, EDTA 2Na,calcium disodium EDTA, EDTA 3Na, EDTA 4Na, EDTA 2K, EDTA 2Li, EDTA 2NH₄,EDTA 3K, Ba(II)-EDTA, Ca(II)-EDTA, Co(II)-EDTACu(II)-EDTA, Dy(III)-EDTA,Eu(III)-EDTA, Fe(III)-EDTA, In(III-EDTA, La(III)-EDTA, CyDTA, DHEG,diethylenetriamine penta acetic acid (DTPA), DTPA-OH, EDDA, EDDP, EDDPO,EDTA-OH, EDTPO, EGTA, HBED, HDTA, HIDA, IDA, Methyl-EDTA, NTA, NTP,NTPO, O-Bistren, TTHA, EGTA, DMSA, deferoxamine, dimercaprol, zinccitrate, a combination of bismuth and citrate, penicillamine, succimeror Etidronate. The chelator may bind barium, calcium, cerium, cobalt,copper, iron, magnesium, manganese, nickel, strontium, or zinc.

V. PATTERNED AND/OR LAYERED FILMS AND COVERINGS

In some embodiments, an antimicrobial covering or film of the presentinvention comprises regions that contain antimicrobial compounds andregions that do not contain antimicrobial compounds. The antimicrobialcovering or film may comprise 2, 3, 4, or more layers. In someembodiments, the antimicrobial covering or film may contain 2 or morelayers, wherein some layers contain antimicrobial compounds and otherlayers do not contain antimicrobial compounds. For example, in someembodiments, the film may comprise three layers including two outerlayers that do not contain antimicrobial compounds and a middle layerthat contains one or more antimicrobial compound(s) (e.g., minocycline,rifampin, GTN, MeSNA, and/or caprylic acid; minocycline and rifampin;minocycline, rifampin, and GTN; minocycline, rifampin, and MeSNA;minocycline, rifampin, MeSNA, and caprylic acid) that are eithercontinuously distributed throughout the middle layer or contained inregions of the middle layer. In some embodiments, the outer layers of alayered film may have either higher melting temperatures and/or improvedhandling properties. In some embodiments, it may be desirable to includethe antimicrobial compound(s) the outer layers of a layered film orcovering. As would be appreciated by one of skill in the art, thepattern of distribution of antimicrobial compounds in regions of a filmor layer of film may be selected as desired; for example, the regionsmay be roughly circular or oval (e.g., in a “polka-dot” pattern),square, striped, etc., as desired. In some embodiments, an antimicrobialfilm or antimicrobial layer of film may contain the antimicrobialcompounds distributed throughout the layer in a sponge-like patternbased on the creation of voids in the film that are subsequently filledwith a filler (e.g., containing or consisting of a highly plasticizedgelatin) comprising the antimicrobial compound(s).

In some embodiments, regions in a film that contain antimicrobialcompound(s) may be introduced into the film, e.g., by removing portionsof the film or creating voids in the film that are subsequently filledwith a molten filler (e.g., a highly plasticized gelatin) that containsthe antimicrobial compound(s). Different shaped and/or sized voids(e.g., windows, textures, sponge-like voids, etc.) may be created in orintroduced into a film or layer of film (e.g., for films that include 2,3, 4, or more layers) as desired. Several methods for creating voids infilms that may be used to generate voids in a film that can subsequentlybe filled with molten bioactive fillers may be used with the presentinvention. For example, in some embodiments, fillers such as salts orsugars may be added to a film and subsequently dissolved away, leavingbehind voids that may subsequently be filled with a composition (e.g.,highly plasticized gelatin) containing the antimicrobial compound(s).

VI. METHOD FOR INCREASING THE WORKING TIMES OF THE FILMS

In some cases it may be desirable to reposition implants comprising orcovered in an antimicrobial film of the present invention followinginitial placement in the body of a subject or human patient. In someembodiments, it may be desirable for films to retain their solidproperties for several minutes to as long as 1 hour to allow for implantrepositioning prior to liquefying. As used herein, the “working time” ofa film generally refers to the amount of time that the film may behandled for before it becomes substantially liquefied; thus, films mayexhibit longer working times, e.g., by exhibiting slower melting orliquefaction at a given temperature (e.g., body temperature) and/orincreased toughness. Liquefaction can involve the combined process ofmelting and hydration. The hydration properties of the implant material(e.g., a highly plasticized gelatin) may be affected by thehydrophilicity of the plasticizer, the hydrophilicity of the bioactiveagents (e.g., if present in high concentrations), and degree ofcrosslinking. For example, greater crosslinking, for example increaseddehydrothermal heat treatment, can result in stiffer (more resistant todeformation), tougher (e.g., less likely tear), and/or dryer materials;since hydration may be involved in the liquefaction process of amaterial, a decreased water content of the film or wrap can result inincreased working times for the material, as the film may liquefy moreslowly due to the decreased water content of the film or wrap material.Additional plasticizer may be included in the material, e.g., to reducethe stiffness with little or no increase in the degree of swelling ofthe material after insertion into a subject such as a human patient. Insome embodiments and as shown in the below examples, a film, covering,or wrap of the present invention may have a working time of more thanone hour.

The working times of an antimicrobial film of the present invention maybe increased by lightly crosslinking the film. Crosslinking methods thatmay be used include, e.g., radiation, dehydrothermal heat treatment, andchemical crosslinking. Chemical crosslinking agents may be used tocrosslink proteins using, e.g., carboxyl, carbonyl, sulfhydryl, amine orhydroxyl reactive agents. Homo bi (or poly) functional or hetero bi (orpoly) functional agents can be used for crosslinking. In addition,enzymes can also be used for crosslinking. Common agents that may beused to promote crosslinking include, e.g., glutaraldehyde, disuccinimide esters of N-hydroxy succinimide (NHS), such as polyethyleneglycol NHS esters, carbo-diimide crosslinkers, maleimides, imidoesters,haloacetyls, pyridyl disulfides, hydrazides, glyoxals, sulfones,periodates, isocynates, ureas, disulfides. Activatable crosslinkers,such as photoactivated crosslinkers, can also be used includingpsoralens, aryl azides or diazirines. Radiation and dehydrothermaltreatment may be preferably used in some embodiments, as they offer thebenefit of not needing to introduce new chemical agents into the films.

Crosslinking of a film may in some embodiments preferably be performedprior to adding antimicrobial compound(s) to the film, sincecrosslinking can potentially adversely affect antimicrobial compound(s)in the film. For example, the heat associated with dehydrothermalcrosslinking treatment can have undesirable impacts on the stability andresidual activity of bioactive agents such as minocycline, rifampin,MeSNA, fatty acids or glycerol nitrates. Similarly, chemicalcrosslinking agents or radiation may react with bioactive agents. Asshown in the below examples, different designs allow incorporation ofbioactive agents into the films subsequent to partial crosslinking. Forexample, preformed pockets may be created in a film that allows foraddition of bioactive agents, e.g., comprised in a formulation with ashorter working time such as, e.g., a gelatin formulation or a highlyplasticized gelatin with a shorter working time, or in another liquid orsolid formulation. As shown in the below examples, the working time andflexibility of films can be adjusted by the duration and temperature ofdehydrothermal treatment, and the ductility can be affected by adjustingthe quantity of plasticizer and/or water remaining in the film.

VII. METHODS FOR REDUCING INFECTION

In various aspects the antimicrobial bioabsorbable films of the presentinvention may be used to reduce or prevent infection or othercomplications, such as capsular contracture, that may be associated withthe implantation of a medical device, such as a breast implant. In someembodiments, infections associated with breast reconstruction, breastimplants, and/or breast tissue expanders may be reduced or substantiallyprevented. The bioabsorbable films may also be used to wrap a portion orall of an implanted device. The wrapping may occur before or during asurgery. In various embodiments, other complications of implanteddevices may be reduced or substantially prevented such as, e.g.,fibrosis, scaring, and/or formation of adhesions.

The following methods are provided as examples for how a wrap, covering,or film of the present invention may be applied to an implant in asurgical pocket. In some embodiments, an implant is fully wrapped withthe substantially solid film prior to inserting it into a surgicalpocket. Alternately, the wrap can be applied to the implant by liningall or part of the surgical pocket with the film and then inserting theimplant into a subject, such as a human patient. In some cases, thebottom or certain portions of the surgical pocket can be lined with filmand then additional film is draped over the top and sides of the implantprior to insertion.

Application of a wrap, film, or covering of the present invention canalso be accomplished by converting a solid film of the present inventioninto a plurality of particles or smaller pieces (e.g., that aresubstantially solid at room temperature and that liquefy in situ at bodytemperature, like the solid film). The particles may be formed bycryomilling the solid film (e.g., a solid gelatin film) or by othermechanical (e.g., chopping, mincing, dicing) processes. Particles canalso be directly formed from the molten gelatin material by dripping,dispersing droplets or emulsifying in a non-solvent, such as an oil orsilicone fluid, and then cooling to solidify. Particles can further beformed by extruding a molten gelatin into thin filaments that arechopped upon cooling. Particles can be directly molded by extruding themolten gelatin into molds with particle shapes or indentations and thencooling. Particles can be directly applied to the implant or in thesurgical pocket prior to placement of an implant. Particles can also besuspended in a volatile non-solvent propellant and then sprayed.Examples of volatile non-solvent propellants are butane, propane,volatile dimethicones and cyclomethicones and hydrofluoroalkanes such astetrafluoroethane, difluoroethane and hexafluoropropane. Particles canalso be suspended in fluids that are absorbable, drain, or evaporate andspread in the surgical pocket or on the implant. Plasticizing agentssuch as aliphatic polyols, sugars, polyethylene glycols and glycerols,aqueous fluids and short chain or unsaturated lipids can be used tofacilitate spreading. A plasticizing agent may be used instead of or incombination with a volatile non-solvent propellant.

VIII. EXAMPLES

The following examples are included to demonstrate preferred embodimentsof the invention. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples which follow representtechniques discovered by the inventor to function well in the practiceof the invention, and thus can be considered to constitute preferredmodes for its practice. However, those of skill in the art should, inlight of the present disclosure, appreciate that many changes can bemade in the specific embodiments which are disclosed and still obtain alike or similar result without departing from the spirit and scope ofthe invention.

Example 1 Fabrication of Highly Plasticized-Gelatin Films

Molten gelatin was made by adding 16 g porcine gelatin to 40 ml waterand dissolving at 80 C. 16 g glycerol was then stirred in to form aplasticized solution. This was poured into a large plate to form a thinlayer of liquid at the bottom and allowed to cool. Upon cooling, thethin film solidified and was peeled off of the plate. It could bewrapped around a silicone breast implant to which it conformed andadhered. The film was placed in a 37 C incubator and checkedperiodically. It remained solid for approximately 10 minutes after whichis became soft and melted to a viscous liquid indicating a working timeof approximately 10 minutes to place the implant from the time it entersthe body.

Example 2 Adhesive Layer on Highly Plasticized Gelatin Film

A film was formed as in Example 1. A separate solution of 8 g gelatin in4 ml water was heated to which was added 2 ml 50% gluconic acid. Thiswas poured on top of the plasticized gelatin film. Upon cooling the topsurface of the plasticized gelatin film was now sticky and veryadhesive.

Example 3 Production of Minocycline/Rifampin Disc

20 ml of plasticized gel was made as described in Example 1. To this wasadded 1.5 ml ethanol containing 20 mg Minocycline and 10 mg Rifampin. Toform a coated test disc, molten plasticized-gel was pipetted into 24well microtiter plates until the bottom of each well was covered(approximately 1-2 mm thick layer of liquid). A solid 2 mm thick, 6 mmdiameter silicone disk (same material as breast implant shells arefabricated with) was placed on top and the plate cooled at roomtemperature for 2 minutes. The film+disk was briefly heated and anotherfilm layer (thickness of approximately 1-2 mm) was placed atop the disk.The gel was allowed to cool at room the ethanol to evaporate. Finallythe film covered discs were removed from the mold and the layers werecut with a 7.5 mm diameter cork borer. This resulted in 7.5 mm test discthat was comprised of a 6 mm diameter silicon disc completely encased inantimicrobial gel wrap with 2 mm on each side of the disc. Films werealso made using 2 mg Rifampin and 1 mg Minocycline.

Example 4 Production of Minocycline/Rifampin/GTN Disc

Another set of test discs were produced using the same method as inExample 3 except 10 mg Glyceryl Trinitrate was combined with the 20 mgMinocycline and 10 mg Rifampin in ethanol prior to being added to themolten plasticized gel. Films were also made where 10 mg GlycerylTrinitrate was combined with 2 mg Rifampin and 1 mg Minocycline.

Example 5 Test to Determine Antimicrobial Efficacy

Both test discs and control silicone discs were independently exposed to1 mL of 5.5×10⁵ CFU of various test microorganisms including methicillinresistant Staphylococcus aureus, Staphylococcus epidermidis, andmultidrug resistant Pseudomonas aeruginosa and incubated for 24 hrs at37 C. Discs were then removed from their fluid wells and washed for 30min shaking in 0.9% sterile saline. To disrupt biofilm, discs were thenplaced in 5 mL of 0.9% sterile saline and sonicated for 15 minutes.Resulting solution was quantitative cultured by serial dilution andpipetted onto tyrpticase soy agar with 5% sheep blood, incubated for 24hrs and counted for growth. Tests were performed in Triplicate. Meansand Standard deviations are presented in the plots below for challengeswith clinical strains of methicillin resistant staphylococcus aureus(MRSA), Pseudomonas aeruginosa and Klebsiela pneumonia. Results areshown in FIG. 1.

The films with 1 mg/ml Minocycline and 0.5 mg/ml Rifampin were able toprevent the gram positive and gram negative organisms tested fromadhering to the silicone. GTN worked synergistically with lower doses ofMinocycline (0.05 mg/ml) and Rifampin (0.1 mg/ml) to protect thesilicone from bacterial colonization.

Example 6 Production of Minocycline/Rifampin/MeSNA Test Disc

Another set of test discs were produced using the same method as inExample 3. 1000 mg of sodium mercaptoethane sulfonate (MeSNA) was addedto the 20 ml molten plasticized gel in addition to 2 mg Minocycline and1 mg Rifampin (low dose M/R) prior to casting. To test synergy, controldisks consisting of MeSNA alone, Minocycline/Rifampin alone and diskswith no additives were formed as well.

Example 7 Antimicrobial Testing

Testing was performed as in Example 5 utilizing clinical strains of MRSAand Pseudomonas aeruginosa to challenge. Quantitative recoveries areshown in FIG. 3.

The combination of MeSNA and low dose M/R reduced adherence of MRSA andPseudomonas aeruginosa over 1 log below either alone.

Example 8 M/R+MeSNA+GTN Discs

Additional discs were made as in Example 6. In addition to MeSNA andM/R, GTN was included as in Example 4.

Example 9 Testing of M/R+MeSNA+GTN Discs

Testing was performed as in Example 6 utilizing a clinical isolate ofMRSA to challenge. Quantitative recoveries for GTN alone, GTN+M/R andGTN+M/R+MeSNA are shown in FIG. 4. MeSNA alone, M/R alone and M/R+MeSNAresults are reported in Example 7.

Results are shown in FIG. 4. Only the M/R+GTN+MeSNA was able tocompletely prevent colonization of the disk surface.

Example 10 M/R+MeSNA+Caprylic Acid Discs

Additional discs were made as in Example 6. In addition to MeSNA andM/R, Caprylic acid at a concentration of 10 mg/ml was included as inExample 4.

Example 11 Testing of M/R+MeSNA+GTN Discs

Testing was performed as in Example 6 utilizing a clinical isolate ofPseudomonas aeruginosa to challenge. Quantitative recoveries for M/Ralone, MeSNA alone, Caprylic acid alone and the combinations MeSNA+M/Rand Caprylic acid+MeSNA+M/R GTN+M/R are shown in FIG. 5.

Results are shown in FIG. 5. Only the (M/R+MeSNA+Caprylic acid) was ableto completely prevent colonization of the disk surface.

Example 12 Method for Assessing Working Times Prior to Melting

The following method for assessing working times prior to melting wasused in following examples. Working times of solid films were assessedby compressing both sides against thick gauze soaked with saline andincubating for specified times at 37 C. The gauze was pre-incubated at37° C. prior to contacting with the films. Following the incubationinterval, the films were removed and tensile strength was assessed bymanually stretching the film to more than 110% of its original lengthand observing whether the film tore or recoiled.

Example 13 Increased Working Time by Dehydrothermal Heat Treatment

A highly plasticized gelatin film was prepared as in Example 1. The filmwas heated in an oven at 175° F. for 2 hours. Following cooling, theworking time of the film was assessed as previously described. The filmhad a working time of approximately 15 minutes.

Example 14 Further Increased Working Time by Dehydrothermal HeatTreatment

A highly plasticized gelatin film was prepared as in Example 1. The filmwas heated in an oven at 175° F. for 2 hours and subsequently at 225° F.for 4 hours. Following cooling, the working time of the film wasassessed. The film had a working time of more than 1 hour. This film wasnoticeably stiffer prior to assessment of working time. During theworking time assessment, the film absorbed moisture and increased inflexibility. Flexibility of the solid film could be restored followingremoval from the oven by allowing exposure to ambient humid air.

Example 15 Increased Working Time with Increased Ductility

A highly plasticized molten gelatin solution was prepared by combining 4g porcine gelatin, 4.8 g glycerol and adding water to 20 ml total volumeat 80° C. The molten solution was cast onto a tray and placed in an ovenat 175° F. for 8 hours. Subsequently the temperature was increased to225° F. for 4 hours. Following cooling, the film was more flexible thanin the previous example. This working time of this film was assessed aspreviously described. This film had a working time of more than 1 hour.

As shown here, the working time and flexibility of films can be adjustedby the duration and temperature of dehydrothermal treatment, as well asby the quantity of plasticizer and/or water remaining in the film.

Example 16 Open Partially Crosslinked Gelatin Film Containing Regions ofMinocycline/Rifampin in Non-Crosslinked Gelatin

A highly plasticized molten gelatin solution was prepared by combining 4g porcine gelatin, 4.8 g glycerol and adding water to 20 ml total volumeat 80° C. The molten solution was cast onto a tray in a thin layer andplaced in an oven at 175° F. for 8 hours. The film was subsequentlycured for 4 hours at 225° F. The resulting film was removed and holeswere punched out such that more than 50% of the surface contained voids.Molten gelatin containing Minocycline and Rifampin was prepared as inExample 3 and cast on top of the void containing layer of film. It wascompression molded to fill in the voids and then allowed to cool. Theresulting film was tested for working time. The structural portion ofthe film retained a working time of 1 hour but was weaker than thecontinuous similar film. The antimicrobial portion melted earlier, ascompared to Example 15, and minocycline and rifampin began to elute fromthe film by one hour. A drawing of a film design containing structuralregions of lightly crosslinked gelatin and regions withMinocycline/Rifampin is shown in FIG. 6.

Example 17 Open Laminate Partially Crosslinked Gelatin Film ContainingRegions of Minocycline/Rifampin in Non-Crosslinked Gelatin

A highly plasticized molten gelatin solution was prepared by combining 4g porcine gelatin, 4.8 g glycerol and adding water to 20 ml total volumeat 80° C. The molten solution was cast onto a tray in a thin layer andplaced in an oven at 175° F. for 8 hours. The resulting film was removedand holes were punched out such that more than 50% of the surfacecontained voids. The film with the voids was placed on top of acontinuous thin film prepared in an analogous manner except withoutholes punched out. The 2 layer laminate was subsequently further curedat 225° F. for 4 hours then removed and allowed to cure. Molten gelatincontaining Minocycline and Rifampin was prepared as in Example 3 andcast on top of the void containing layer of the cool 2-layer film. Itwas compression molded to fill in the voids and then allowed to cool.Following cooling the resulting film was tested for working time. Therewas 1 hour working time and with no delamination of the two structurallayers. The tensile strength of the laminate was greater than in theprevious example. The antimicrobial regions melted before the structuralpart. As long as the continuous layer was on bottom the antimicrobialregion did not flow out of the film.

Example 18 Closed Laminate Partially Crosslinked Gelatin Film ContainingRegions of Minocycline/Rifampin in Non-Crosslinked Gelatin

A highly plasticized molten gelatin solution was prepared by combining 4g porcine gelatin, 4.8 g glycerol and adding water to 20 ml total volumeat 80° C. The molten solution was cast onto a tray in a thin layer andplaced in an oven at 175° F. for 8 hours. The resulting film was removedand holes were punched out such that more than 50% of the surfacecontained voids. The film with the voids was placed on top of acontinuous thin film prepared in an analogous manner except withoutholes punched out. Then a continuous film was placed on top of the openside. The 3 layer laminate was subsequently further cured at 225° F. for4 hours then removed and allowed to cure. Molten gelatin containingMinocycline and Rifampin was prepared as in Example 3 and injectedthrough a short needle into the void spaces in the middle of the cool3-layer film. It was then allowed to cool. Following cooling theresulting film was tested for working time. There was 1 hour workingtime and with no delamination of the three structural layers. Theenclosed laminated fully contained the antimicrobial regions during theworking time assessment. This design is illustrated in FIG. 7.

It will be apparent to one of ordinary skill in the art that differentshape and size voids (including windows) could be used in these laminateconstructs. Other methods of creating voids in films exist that may beused to generate voids in a film that can subsequently be filled withmolten bioactive fillers. One is to add fillers such as salts or sugarsthat can be subsequently dissolved away, leaving behind voids.

Example 19 3-Layer Sandwich Laminate

A highly plasticized molten gelatin solution was prepared by combining 4g porcine gelatin, 4.8 g glycerol and adding water to 20 ml total volumeat 80° C. The molten solution was cast onto a tray and placed in an ovenat 175° F. for 8 hours. Subsequently the temperature was increased to225° F. for 4 hours, the film removed and allowed to cool. Moltengelatin containing Minocycline and Rifampin was prepared as in Example 3and poured on top of a thin film of crosslinked gelatin. A second filmof crosslinked gelatin was placed on top and the middle layer wascompression molded into a thin film between the outer layers. Thelaminate was allowed to cool forming a solid film.

Example 20 Single Layer Reinforced Film

A highly plasticized molten gelatin solution was prepared by combining 4g porcine gelatin, 4.8 g glycerol and adding water to 20 ml total volumeat 80° C. The molten solution was extruded into filaments that wereplaced onto a tray which was placed in an oven at 175° F. for 8 hours.Subsequently the temperature was increased to 225° F. for 4 hours, thefilaments removed and allowed to cool. The filaments were lain acrossone another as a dense mat. Molten gelatin containing Minocycline andRifampin was prepared as in Example 3 and compression molded into themat of filaments. The film was allowed to cool forming a meltablefilament reinforced film.

Example 21 Filled Sponge

A highly plasticized molten gelatin solution was prepared by combining 4g porcine gelatin, 4.8 g glycerol and adding water to 20 ml total volumeat 80° C. Cellulose acetate particles were dispersed to form a densesuspension. Molten suspension was compressed into a film onto a tray andplaced in an oven at 175° F. for 8 hours. Subsequently the temperaturewas increased to 225° F. for 4 hours, the film removed and allowed tocool. The film was then immersed in acetone solution dissolving away theparticles and leaving a sponge. The sponge was rinsed and allowed tofully dry. Molten gelatin containing Minocycline and Rifampin wasprepared as in Example 3 and injected through a needle into the spongefilling the interstices. The filled sponge was allowed to cool.

A highly plasticized molten gelatin solution was prepared by combining 4g porcine gelatin, 4.8 g glycerol and adding water to 20 ml total volumeat 80° C. Ethyl cellulose particles were dispersed to form a densesuspension. Molten suspension was compressed into a film onto a tray andplaced in an oven at 175° F. for 8 hours. Subsequently the temperaturewas increased to 225° F. for 4 hours, the film removed and allowed tocool. The film was then immersed in diluted acetone solution dissolvingaway the particles and leaving a sponge. The sponge was allowed to fullydry. Molten gelatin containing Minocycline and Rifampin was prepared asin Example 3 and injected through a needle into the sponge filling theinterstices. The filled sponge was allowed to cool.

Example 22 Wrap Cytotoxicity Testing

Preparation of Solid Film Wraps

Silicone disks covered with plasticized gelatin films were formed as inExample 3. High concentration Minocycline (M) and Rifampin (R) filmswere created with a final concentration of 0.1% M and 0.05% R (highM/R), while low concentration M/R films were created with 0.01% M and0.005% R (low M/R). In some experiments, MESNA was also added to a finalconcentration of 5%.

Cytotoxicity Tests

A human fibroblast (HEK-293T) cell-line was maintained in Dulbecco'smodified Eagle's medium (DMEM) (MediaTech Inc., Manassas, Va.)supplemented with 10% heat-inactivated fetal bovine serum (FBS) (SigmaCo., St. Louis, Mo.), in 5% CO₂ at 37° C. 293T cells were passaged twiceper week. Cells were plated at a density of 5×10⁵ cells/well in 48-wellculture plates using a cell counter (Z1 Coulter Particle Counter,Beckman Coulter). At 50% confluence, discs wrapped with the previouslydescribed combinations of M, R and MeSNA were added into the wells.Gelatin wrapped discs (no antimicrobial agents) and medium were usedcontrols. After 24 hrs, drug induced cell viability and toxicity wasassessed by Alamar blue and MTT(3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assaysrespectively.

1. Alamar Blue Assay:

Alamar blue assay (Life Technologies Corp., Carlsbad, Calif.) wasperformed to assess sensitivity of the drug impregnated gelatin discs tocells. This assay is based on reduction of the indicator dye, resazurin,to the highly fluorescent resorufin in corresponding to metabolicallyactive cells. Drug sensitized cells rapidly lose their metaboliccapacity in the reduction of resazurin and thus produce no fluorescentsignal. Briefly, after 24 hr of treatment, plate was centrifuged andmedium was replaced with DMEM+5% FBS without phenol red. Alamar bluereagent (50 ul) was directly added to cells in the culture medium andincubated for 3 hr at 37° C. Absorbance was determined at 570 nm usingUV visible spectrophotometer (BioTek Instruments, Inc., Winooski, Vt.).Inhibition of cell viability was compared with untreated control cells.Results are expressed as percentage of survival normalized to untreatedcontrols. All experiments were performed in triplicate.

2. MTT Assay:

In vitro cytotoxicity was assessed quantitatively by monitoring themitochondrial reduction activity of viable cells using the MTT assay(Sigma Co., St. Louis, Mo.). The bioactive agent treatment protocolfollowed in the Alamar blue assay was followed here as well. After 24 hrof treatment, plates were centrifuged and medium was replaced withDMEM+5% FCS without phenol red. MTT solution was added to 10% of theculture medium and incubated at 37° C. for 3 hr. MTT solvent was addedto dissolve formazan crystals and absorbance of the dissolved materialswas measured at 570 nm spectrometrically using a UV Visspectrophotometer (BioTek Instruments, Inc., Winooski, Vt.). Bioactiveagent induced toxicity from treated cells were determined by comparisonof signals from untreated control cells. Results are expressed aspercentage of surviving cells relative to controls. Experiments wereperformed in triplicate.

As shown in FIGS. 8A-B, the control gelatin wrapped disks had no adverseeffect on the viability of 293T cells relative to cells grown in broth.From both the Alamar blue (FIG. 8A) and MTT assays (FIG. 8B), gelatinwrapped disks containing MeSNA, Low M/R, High M/R and MeSNA+Low M/R didnot produce a significant reduction in cell viability compared to cellsgrown in broth (P=0.74). Results are shown in FIG. 8.

Example 23 Antimicrobial Crosslinked Wrap Made by Method of SoakingCrosslinked Wrap in Antibiotic Solution then Drying

A highly plasticized molten gelatin solution was prepared by combining 4g porcine gelatin, 4.8 g glycerol and adding water to 20 ml total volumeat 80° C. The molten solution was cast onto a tray in a thin layer andplaced in an oven at 175° F. for 8 hours. The film was subsequentlycured for 2 hours at 225° F. to dehydrothermally crosslink it and it wasallowed to cool. 20 mg Minocycline and 10 mg Rifampin was dissolved in 1ml ethanol. The volume was increased to 20 ml by adding water. A thincoating of solution was layered on top of the film. The film absorbedsome of the liquid and turned orange reflecting absorption of theantibiotics. Excess liquid was poured off and the film was allowed toevaporatively dry. The antibiotic-loaded crosslinked wrap returned toits original thickness and retained its original ductility but hadtexturing on the surface of the solution side.

Example 24 Method of Extending Release from Antimicrobial CrosslinkedWrap Made by Method of Soaking Crosslinked Wrap in Antibiotic Solutionthen Drying then Further Heat Treating

A highly plasticized molten gelatin solution was prepared by combining 4g porcine gelatin, 4.8 g glycerol and adding water to 20 ml total volumeat 80° C. The molten solution was cast onto a tray in a thin layer andplaced in an oven at 175° F. for 8 hours. The film was subsequentlycured for 2 hours at 225° F. to dehydrothermally crosslink it and it wasallowed to cool. 40 mg Minocycline and 20 mg Rifampin was dissolved in 1ml ethanol. The volume was increased to 20 ml by adding water. A thincoating of solution layered on top of the film. The film absorbed someof the liquid and turned orange reflecting absorption of theantibiotics. Excess liquid was poured off and the film was allowed toevaporatively dry. A 1 inch square of film was placed in petri dish. Asecond 1 inch square piece from the remaining dry film was further heattreated at 60° C. for 4 hr and then cooled. This was placed in aseparate Petri dish. 10 m saline was added to both petri dishes whichwere incubated at 37° C. for 2 hours. Absorbance at 550 nm was readusing a spectrophotometer. The liquid from the 60° C. heat treatedsample had less absorbance than the other and the remaining filmretained more color intensity.

Example 25 Antimicrobial 2-Layer Wrap Made by Method of CoatingCrosslinked Wrap in Antibiotic Gelatin Solution

A highly plasticized molten gelatin solution was prepared by combining 4g porcine gelatin, 4.8 g glycerol and adding water to 20 ml total volumeat 80° C. The molten solution was cast onto a tray in a thin layer andplaced in an oven at 175° F. for 8 hours. The film was subsequentlycured for 2 hours at 225° F. to dehydrothermally crosslink it and it wasallowed to cool. 40 mg Minocycline and 20 mg Rifampin was dissolved in 1ml ethanol. This was added to 19 ml of 30% gelatin/glycerol with agelatin:glycerol ratio of 50:50. A thin coating of solution was spreadon top of a prewarmed film (45° C.). The film absorbed some of theliquid and turned orange reflecting absorption of the antibiotics. Thefilm set and was allowed to evaporatively dry. The coated,antibiotic-loaded crosslinked wrap retained its original ductility. Athin layer of coating solution was also spread on a crosslinked filmfrom the previous example which had been preloaded with antibiotics. Thecoated film cooled and was allowed to evaporatively dry where itretained its original ductility.

Example 26 Antimicrobial 3-Layer Sandwich Laminate Made by Heat SealingEdges

A highly plasticized molten gelatin solution was prepared by combining 8g porcine gelatin, 9.6 g glycerol and adding water to 40 ml total volumeat 80° C. The molten solution was cast onto 2 trays and placed in anoven at 175° F. for 8 hours. Subsequently the temperature was increasedto 225° F. for 2 hours, the film removed and allowed to cool. Moltengelatin containing Minocycline and Rifampin was prepared as in Example 3and a volume poured on top of a thin film of crosslinked gelatin. Asecond film of crosslinked gelatin was placed on top and the middlelayer was compression molded into a thin film such that the outer layersextended beyond the edges of the antibiotic-containing middle layerwhich overlapped each other. The laminate was allowed to cool. Focusedhigh intensity heat was applied using a heat gun to the overlappingedges of the non-antibiotic layers until they welded together forming aseal all around the circumference.

Example 27 Method of Application of Wrap to Transcutaneous Devices onBoth Internal and External Surfaces

Surgical drains are examples of transcutaneous devices that haveportions on the subcutaneous side as well as the epidermal side of theskin. The subcutaneous side of the drain can be wrapped prior to closureof the surgical site and following closure the external side can bewrapped and secured with an adhesive dressing. Alternatively, the wrapcan be applied to the skin round the exit site and secured with adressing.

All of the methods disclosed and claimed herein can be made and executedwithout undue experimentation in light of the present disclosure. Whilethe compositions and methods of this invention have been described interms of preferred embodiments, it will be apparent to those of skill inthe art that variations may be applied to the methods and in the stepsor in the sequence of steps of the method described herein withoutdeparting from the concept, spirit and scope of the invention. Morespecifically, it will be apparent that certain agents which are bothchemically and physiologically related may be substituted for the agentsdescribed herein while the same or similar results would be achieved.All such similar substitutes and modifications apparent to those skilledin the art are deemed to be within the spirit, scope and concept of theinvention as defined by the appended claims.

The invention claimed is:
 1. A biodegradable covering for a medicalimplant, the covering comprising a highly plasticized gelatin and atleast one drug to reduce infection or capsular contraction, wherein theplasticized gelatin has a melting temperature of less than 38° C., andwherein the plasticized gelatin consists essentially of gelatin and fromgreater than 40% to about 60% plasticizer.
 2. The covering of claim 1,wherein the plasticized gelatin has a melting temperature of 27-37° C.3. The covering of claim 1, wherein the plasticized gelatin has amelting temperature of 30-37° C.
 4. The covering of claim 2, wherein theplasticized gelatin comprises about 50-55% plasticizer.
 5. The coveringof claim 4, wherein the plasticizer is glycerol, a propylene glycol, asugar, a carbohydrate, an amino acid, a salt, an acid, or a polyol. 6.The covering of claim 5 wherein the plasticizer is glycerol.
 7. Abiodegradable covering for a medical implant, the covering comprising ahighly plasticized gelatin and at least one drug to reduce infection orcapsular contraction, wherein the plasticized gelatin has a meltingtemperature of less than 38° C., wherein at least a portion of a surfaceof the covering has been treated with a gluconic acid solution.
 8. Thecovering of claim 1, wherein at least a portion of a surface of thecovering has been treated with a glycerol-gelatin liquid comprisingabout 60-90% glycerol or a solution comprising a carbohydrate, a starch,or a sugar.
 9. The covering of claim 1, wherein the covering issufficient in size or shaped to cover a breast implant.
 10. The coveringof claim 9, wherein the covering is shaped as a film, a wrap, a pouch ora bag.
 11. A biodegradable covering for a medical implant, the coveringcomprising a highly plasticized gelatin and at least one drug to reduceinfection or capsular contraction, wherein the plasticized gelatin has amelting temperature of less than 38° C.; wherein the covering issufficient in size or shaped to cover a breast implant; wherein thecovering is shaped as a film, a wrap, a pouch or a bag; and wherein thecovering is a pouch or a bag; wherein the covering has a central regionand a plurality of lateral appendages, or the covering is substantiallystar-shaped.
 12. The covering of claim 1, wherein the covering comprisesa plurality of biodegradable layers.
 13. The covering of claim 1,wherein the at least one drug is selected from the group consisting ofan antimicrobial agent, an anti-inflammatory agent, an anti-scarringagent, a hemostatic agent, an anti-neoplastic agent, a calcium channelblocker, and a leukotriene inhibitor.
 14. The covering of claim 13,wherein the at least one drug is an antimicrobial agent.
 15. Thecovering of claim 14, wherein the antimicrobial agent is bacitracin,cephalexin, gentamicin, an antiseptic, a chelator, chlorhexidine,gendine, gardine, a leukotriene inhibitor, hydrogen peroxide, anitroglycerin, or a nitric oxide donor.
 16. The covering of claim 1,wherein the covering comprises at least one of mercaptoethane sulfonate(MeSNA), minocycline, rifampin, or glyceryl trinitrate (GTN).
 17. Thecovering of claim 16, wherein the covering comprises at least two ofmercaptoethane sulfonate (MeSNA), minocycline, rifampin, and/or glyceryltrinitrate (GTN).
 18. The covering of claim 17, wherein the coveringcomprises minocycline, rifampin, and mercaptoethane sulfonate.
 19. Abiodegradable covering for a medical implant, the covering comprising ahighly plasticized gelatin and at least one drug to reduce infection orcapsular contraction, wherein the plasticized gelatin has a meltingtemperature of less than 38° C.; wherein the covering comprisesminocycline, rifampin, and mercaptoethane sulfonate; and wherein thecovering further comprises glyceryl trinitrate (GTN), a monoglyceride,or a fatty acid.
 20. The covering of claim 19, wherein the fatty acid isa C₆₋₁₂ alkanoic acid.
 21. The covering of claim 20, wherein the fattyacid is caprylic acid (octanoic acid).
 22. The covering of claim 19,wherein the covering further comprises glyceryl trinitrate (GTN) andcaprylic acid.
 23. The covering of claim 1, wherein at least a portionof the covering has been exposed to crosslinking.
 24. A biodegradablecovering for a medical implant, the covering comprising a highlyplasticized gelatin and at least one drug to reduce infection orcapsular contraction, wherein the plasticized gelatin has a meltingtemperature of less than 38° C.; wherein at least a portion of thecovering has been exposed to crosslinking; and wherein the coveringcomprises regions that have been exposed to crosslinking and regionsthat have not been exposed to crosslinking.
 25. The covering of claim24, wherein the regions that have not been exposed to crosslinkingcomprise minocycline, rifampin, glyceryl trinitrate (GTN),mercaptoethane sulfonate (MeSNA), or caprylic acid.
 26. The covering ofclaim 1, wherein the covering comprises multiple layers.
 27. Abiodegradable covering for a medical implant, the covering comprising ahighly plasticized gelatin and at least one drug to reduce infection orcapsular contraction, wherein the plasticized gelatin has a meltingtemperature of less than 38° C.; wherein the covering comprises multiplelayers; and wherein the covering comprises a first layer comprising apartially crosslinked plasticized gelatin and a second layer comprisinga plasticized gelatin that has not been crosslinked, wherein the secondlayer comprises the drug.
 28. A biodegradable covering for a medicalimplant, the covering comprising a highly plasticized gelatin and atleast one drug to reduce infection or capsular contraction, wherein theplasticized gelatin has a melting temperature of less than 38° C.;wherein the highly plasticized gelatin is comprised on an adhesivebacking.
 29. A kit comprising a breast implant and the biodegradablecovering of claim
 1. 30. A breast implant assembly comprising abiodegradable covering of claim 1 containing a breast implant.
 31. Amethod for reducing at least one post-surgical indication from breastaugmentation or breast reconstruction in a subject, the methodcomprising surgically implanting into the subject the breast implantassembly of claim
 30. 32. A transcutaneous device assembly comprising abiodegradable covering of claim 1 that is wrapped around at least aportion of the transcutaneous device.
 33. A method for reducing at leastone post-surgical indication from implantation of a transcutaneousdevice in a subject, the method comprising surgically implanting intothe subject the transcutaneous device assembly of claim 32.